Lupus nephritis (LN) one of a number of proteinuric kidney diseases wherein an inflammation of the kidneys is caused by systemic lupus erythematosus (SLE) whereby up to 60% of SLE patients develop LN. LN is a debilitating and costly disease often leading to renal failure which requires dialysis, or renal transplant and often results in death. Indeed, patients with renal failure have an over 60-fold increased risk of premature death compared to SLE patients in general. A clinical sign of LN is leakage of blood proteins into the urine and the disease can be diagnosed by a number of factors, including urinary protein/creatinine ratio (UPCR) wherein a UPCR of greater than 0.5 mg/mg is indicative of the condition being in an active state. Further, certain markers in the blood can also be diagnostic—for example, complement 3 (C3), complement 4 (C4) and anti-dsDNA antibodies.
The standard of care for LN has not met with a great deal of success. The standard of care is use of mycophenolate mofetil (MMF) or intravenous cyclophosphamide. With these treatments partial remission was found only in approximately 50% of cases and complete remission was shown in less than 10% of the subjects. Thus, there is clearly a need for a treatment that improves these outcomes.
Voclosporin is an analog of cyclosporin A that has been found useful for treating autoimmune diseases and as an immunosuppressant in organ transplantation.
Mixtures of the E and Z isomers of voclosporin are described in U.S. Pat. No. 6,998,385. Mixtures with a preponderance of the E-isomer are described in U.S. Pat. No. 7,332,472. The '472 patent describes a number of indications which can be treated with the isomeric voclosporin mixture including glomerulonephritis. However, although some animal studies are described, no protocols in humans are disclosed.
Various formulations of voclosporin mixtures are also described in U.S. Pat. Nos. 7,060,672; 7,429,562 and 7,829,533.
In October 2016, the results of a clinical study conducted on behalf of Aurinia Pharmaceuticals were published as an abstract. According to the abstract, the subjects, who were afflicted with lupus nephritis (LN), were dosed with 23.7 mg of voclosporin twice daily in combination with mycophenolate mofetil (MMF) and reducing cortical steroid dose over 24 weeks for which data were presented. Entry criteria for the study included determination of a urine protein creatinine ratio (UPCR) of ≥1.0 mg/mg or ≥1.5 mg/mg depending on the classification of a renal biopsy and an eGFR (estimated glomerular filtration rate) of ≥45 mol/mn/1.73 m2 as well as serologic evidence of LN. The results of this protocol showed complete remission or partial remission in a large percentage of subjects.
In addition, it was shown that subjects who achieved a ≥25% reduction in UPCR at 8 weeks were likely to maintain benefit throughout the 24-week protocol.
In a news release sent by Aurinia Pharmaceuticals on 1 Mar. 2017, the results of more extensive clinical study involving mycophenolate mofetil (MMF) and reducing corticosterone dosages, but using in addition to 23.7 mg of voclosporin twice daily, a higher dose of 39.5 mg twice daily were described. The results of this study showed successful complete or partial remission in a large number of patients at 24 weeks and 48 weeks. It appeared that the lower dosage of 23.7 mg twice daily (BID) was even more effective than the higher dosage of 39.5 mg twice daily (BID).
It has now been found that successful results, including a diminution in the number and severity of side effects can be obtained by altering the protocols disclosed in these publications by providing a pharmacodynamic dosing schedule based on individual patient responses. In addition, it has been found that even lower dosages of voclosporin—i.e., 15.8 mg of voclosporin twice daily or 7.9 mg of voclosporin twice daily are effective.